Organs-on-chips, also known as "tissue chips" or microphysiological systems (MPS), are bioengineered microsystems capable of recreating aspects of human organ physiology and function and are in vitro tools with multiple applications in drug discovery and development. The ability to recapitulate human and animal tissues in physiologically relevant three-dimensional, multi-cellular environments allows applications in the drug development field, including; (1) use in assessing the safety and toxicity testing of potential therapeutics during early-stage preclinical drug development; (2) confirmation of drug/therapeutic efficacy in vitro; and (3) disease modeling of human tissues to recapitulate pathophysiology within specific subpopulations and even individuals, thereby advancing precision medicine efforts. This chapter will discuss the development and evolution of three-dimensional organ models over the past decade, and some of the opportunities offered by MPS technology that are not available through current standard two-dimensional cell cultures, or three-dimensional organoid systems. This chapter will outline future avenues of research in the MPS field, how cutting-edge biotechnology advances are expanding the applications for these systems, and discuss the current and future potential and challenges remaining for the field to address.